Lapatinib ditosylate monohydrate, tablet, 250mg (base), Tykerb, July 2007
Public summary document for Lapatinib ditosylate monohydrate, tablet, 250mg (base), Tykerb, July 2007
Page last updated: 09 November 2007
PDF version of this page (PDF 42KB)
Public Summary Document
Product: Lapatinib ditosylate monohydrate, tablet, 250mg (base), Tykerb
Sponsor: GlaxoSmithKline Australia Pty Ltd
Date of PBAC Consideration: July 2007
1. Purpose of Application
The submission sought a section 100 (Highly Specialised Drug) listing for lapatinib
for use in combination with capecitabine, for the treatment of patients with advanced
or metastatic breast cancer whose tumours overexpress HER2 (ErbB2) and who have received
prior therapy including trastuzumab.
Highly Specialised Drugs are medicines for the treatment of chronic conditions, which,
because of their clinical use or other special features, are restricted to supply
to public and private hospitals having access to appropriate specialist facilities.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Lapatinib was TGA registered on 28 June 2007 for the treatment, in combination with
capecitabine, of patients with advanced/metastatic breast cancer whose tumours overexpress
HER2 (ErbB2) and whose tumours have progressed after treatment with an anthracycline,
a taxane and trastuzumab.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drug) Private hospital authority required
A revised use in combination with capecitabine for the treatment of patients with
advanced /metastatic breast cancer whose tumours overexpress HER2 (ErbB2) and whose
tumours have progressed after treatment with an anthracycline, a taxane and trastuzumab.
The PBAC noted that the submission sought to list lapatinib for second line use in
patients with HER2 positive breast cancer who had failed trastuzumab in the metastatic
setting, but that the restriction proposed did not so limit its use and would allow
lapatinib to be used first line in the metastatic setting after any use of trastuzumab
for early breast cancer.
The PBAC considered that the restriction should be modified to specify that the patient
had either failed trastuzumab in the metastatic setting or had experienced disease
progression while receiving, or shortly after completing adjuvant trastuzumab treatment.
The restriction should also specify that lapatinib must not be used in combination
with trastuzumab, or with any chemotherapy other than capecitabine and that evidence
of HER2 status consistent with the listing for adjuvant trastuzumab must be supplied
to Medicare Australia prior to authority approval. A continuation rule may also need
to be developed. The Committee agreed that a Section 85 listing is appropriate and
noted that the sponsor is willing to negotiate on the restriction wording.
5. Clinical Place for the Proposed Therapy
In recent years, the advent of targeted therapies has offered new treatment options
for breast cancer patients. In Australia, trastuzumab has become the standard treatment
for women with HER2 (ErbB2) overexpressing breast cancer in the metastatic and early
breast cancer setting. Overexpression of HER2 has been associated with poor prognosis
and reduced overall survival.
While a proportion of patients diagnosed with HER2 (ErbB2) overexpressing breast cancer
who take trastuzumab will no longer go on to develop more advanced forms of the disease,
there continues to be a clinical need for additional treatment options for those patients
whose disease progresses to advanced or metastatic breast cancer.
Lapatinib is a small molecule reversible tyrosine kinase inhibitor that targets both
the epidermal growth factor receptor (EGFR) and the HER2 receptor. It will provide
a treatment option for patients who need an additional treatment following trastuzumab.
6. Comparator
The submission nominated both capecitabine monotherapy and trastuzumab plus capecitabine
as comparators.
The PBAC agreed that capecitabine monotherapy was an appropriate comparator, but did
not agree that capecitabine plus trastuzumab was also an appropriate comparator.
7. Clinical Trials
The submission presented one randomised trial comparing lapatinib (1250 mg/day) continuously
plus capecitabine (2000 mg/m2/day on days 1 – 14 of every 21 days) with capecitabine
monotherapy (2500 mg/m2/day on days 1 – 14 of every 21 days) in patients who have
failed treatment with trastuzumab in the metastatic setting.
This trial had been published at the time of submission, as follows:
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
EGF100151 |
Lapatinib plus capecitabine for HER2-positive advanced breast cancer. |
N Engl J Med. 2006 Dec 28;355(26):2733-2743 |
The submission does not provide any evidence of the comparative efficacy and safety
of lapatinib plus capecitabine versus trastuzumab plus capecitabine.
8. Results of Trials
The population recruited to trial EGF100151 were eligible for treatment with lapatinib
if they had HER2 positive locally advanced or metastatic breast cancer that had progressed
after treatment with regimes that included an anthracycline, a taxane and trastuzumab.
Trastuzumab administered in the adjuvant setting was not exclusionary, but, for eligibility,
trastuzumab must also have been administered in the locally advanced or metastatic
setting.
An independent review committee for study EGF100151 was responsible for reviewing
the time to progression (TTP) primary outcome measure data. Assessment intervals for
TTP measurements were pre-specified in the study protocol, and assessors were blinded
to treatment arm and subject outcome.
The published results of the trial are summarised below.
Time To Progression (TTP) evaluated by independent review in Trial EGF100151 (according
to analysis performed after discontinuation of study) as reported in submission
|
Lapatinib + capecitabine |
Capecitabine monotherapy |
Difference |
|
|---|---|---|---|
|
Progression and death (median follow-up not specified), n (%)
|
82 (41) |
102 (51) |
-10% |
|
Cumulative incidence estimate of TTP, in weeks |
27.1 |
18.6 |
8.5 |
|
Hazard ratio |
0.57 (0.43, 0.77) |
||
Overall survival (OS) in Trial EGF100151 (according to analysis performed after discontinuation of study) as reported in submission
|
Lapatinib + capecitabine |
Capecitabine monotherapy |
|
|---|---|---|
|
Kaplan-Meier estimate of OS in weeks |
67.7 (58.9, 91.6) |
66.6 (49.1, 75.0) |
|
Hazard ratio |
0.78 (0.55, 1.12) |
|
Although the surrogate outcome of time to progression reached statistical significance,
there was no statistically significant difference in overall survival between the
lapatinib+capecitabine and capecitabine alone arms.
The study was terminated early by the independent monitoring board due to the positive
findings in time to progression for the lapatinib+capecitabine treated patients. All
subjects were provided access to treatment with lapatinib following termination of
the study. The early termination of the study reduces the likelihood of detecting
a significant difference in overall survival.
The most common adverse events reported in trial EGF100151, regardless of duration
of exposure, were diarrhoea, palmar-plantar erythrodysaesthesia (PPE), nausea (distinct
from PPE), rash and fatigue. Most adverse events were grade 1 or 2, the incidence
of serious adverse events (4%) and discontinuations due to adverse events (12-13%)
were similar in the lapatinib plus capecitabine and capecitabine alone treatment groups.
Statistically significant higher incidences of diarrhoea, rash and dyspepsia were
reported in the lapatinib plus capecitabine group compared with the capecitabine monotherapy
group.
Left ventricular ejection fraction (LVEF) was reduced in 6 women in the lapatinib
plus capecitabine versus 1 in the capecitabine monotherapy group.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission to PBAC claimed that lapatinib plus capecitabine has significant advantages
in effectiveness over capecitabine and no greater toxicity.
For PBAC view of this claim, see Recommendation and Reasons.
10. Economic Analysis
The submission presented a stepped economic evaluation. The choice of a cost-utility
approach was considered valid. However, the PBAC considered the inclusion of trastuzumab
plus capecitabine as a main comparator inappropriate. The resources included were
drug costs and specialist visits.
The incremental discounted costs per additional life year (LYG) or quality adjusted
life year gained (QALY) for lapatinib plus capecitabine versus capecitabine alone
both fell in the range $45,000 - $75,000 when the cost of continuing trastuzumab (even
after progression had occurred while on it) was taken into account. When the cost
of continuing trastuzumab was excluded, the costs per LYG or QALY fell in the range
$110- $200,000.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated that in Year 1 of listing the financial cost/year to the PBS would be in the range $10 – $30 million.
12. Recommendation and Reasons
The Committee agreed that there is some evidence that lapatinib plus capecitabine
improves survival compared to capecitabine alone in patients with HER2 positive metastatic
disease which has progressed despite treatment with trastuzumab, but that the full
extent of this survival benefit is not known and although it is trending towards a
significant result, it is not statistically significant.
The PBAC also concluded that lapatinib plus capecitabine is associated with a higher
incidence of diarrhoea, rash and dyspepsia compared to capecitabine alone
The PBAC agreed that capecitabine monotherapy was an appropriate comparator, but did
not agree that capecitabine plus trastuzumab was also an appropriate comparator. When
used in combination with chemotherapy in metastatic breast cancer, trastuzumab is
most commonly combined with a taxane, vinorelbine or platinum. Additionally, statistics
from the Herceptin Program (the non-PBS trastuzumab metastatic disease program) indicate
that approximately half of patients in the advanced setting are treated with trastuzumab
as monotherapy.
The Committee further considered that the use of trastuzumab as a cost offset in the
stepped economic evaluation rests on inadequately supported assumptions and as the
cost-effectiveness of continuing trastuzumab in patients whose metastatic disease
has progressed despite treatment with trastuzumab is unknown an analysis including
such continuation does not provide an appropriate basis for determining the cost-effectiveness
of lapatinib.
The PBAC thus considered that the most reliable current estimate of the cost-effectiveness
of lapatinib per discounted cost per additional discounted life-year gained (LYG)
or per discounted quality adjusted life year (QALY) over 5 years fell in the range
$110,000 - $200,000. These were considered unacceptably high by the Committee.
The PBAC therefore rejected the submission on the basis of an unacceptable cost effectiveness
ratio.
Recommendation
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor disagrees with the conclusions of the Committee and is disappointed with
the decision. All options will continue to be explored to secure funding for lapatinib,
to ensure access for patients at the earliest possible opportunity.
